IL159404A - Pharmaceutical formulation having a masked taste and method for the production thereof - Google Patents
Pharmaceutical formulation having a masked taste and method for the production thereofInfo
- Publication number
- IL159404A IL159404A IL159404A IL15940403A IL159404A IL 159404 A IL159404 A IL 159404A IL 159404 A IL159404 A IL 159404A IL 15940403 A IL15940403 A IL 15940403A IL 159404 A IL159404 A IL 159404A
- Authority
- IL
- Israel
- Prior art keywords
- active principle
- formulation
- formulation according
- matrix
- adsorbent
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 239000000203 mixture Substances 0.000 claims description 31
- 238000009472 formulation Methods 0.000 claims description 27
- 239000011159 matrix material Substances 0.000 claims description 22
- 229920000642 polymer Polymers 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 125000005395 methacrylic acid group Chemical group 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000003463 adsorbent Substances 0.000 claims description 11
- 230000000873 masking effect Effects 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000005995 Aluminium silicate Substances 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 claims description 6
- 229910000323 aluminium silicate Inorganic materials 0.000 claims description 6
- 235000012211 aluminium silicate Nutrition 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 239000000796 flavoring agent Substances 0.000 claims description 6
- 235000003599 food sweetener Nutrition 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 239000003765 sweetening agent Substances 0.000 claims description 6
- 229960003250 telithromycin Drugs 0.000 claims description 6
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical group O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 claims description 6
- 239000003120 macrolide antibiotic agent Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 229940127557 pharmaceutical product Drugs 0.000 claims description 5
- 239000003755 preservative agent Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 239000002562 thickening agent Substances 0.000 claims description 5
- 229930186147 Cephalosporin Natural products 0.000 claims description 4
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 4
- 230000003115 biocidal effect Effects 0.000 claims description 4
- 229940124587 cephalosporin Drugs 0.000 claims description 4
- 150000001780 cephalosporins Chemical class 0.000 claims description 4
- 230000002209 hydrophobic effect Effects 0.000 claims description 4
- 239000003835 ketolide antibiotic agent Substances 0.000 claims description 4
- 229960003194 meglumine Drugs 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- 229930182555 Penicillin Natural products 0.000 claims description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 3
- 239000004098 Tetracycline Substances 0.000 claims description 3
- 239000007900 aqueous suspension Substances 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 229940049954 penicillin Drugs 0.000 claims description 3
- 239000001508 potassium citrate Substances 0.000 claims description 3
- 229960002635 potassium citrate Drugs 0.000 claims description 3
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 3
- 235000011082 potassium citrates Nutrition 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- 229960002180 tetracycline Drugs 0.000 claims description 3
- 229930101283 tetracycline Natural products 0.000 claims description 3
- 235000019364 tetracycline Nutrition 0.000 claims description 3
- 150000003522 tetracyclines Chemical class 0.000 claims description 3
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000008135 aqueous vehicle Substances 0.000 claims description 2
- 229920006317 cationic polymer Polymers 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229960003646 lysine Drugs 0.000 claims description 2
- 150000002734 metacrylic acid derivatives Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940083542 sodium Drugs 0.000 claims description 2
- 229920003174 cellulose-based polymer Polymers 0.000 claims 5
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 230000003078 antioxidant effect Effects 0.000 claims 2
- 239000004014 plasticizer Substances 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 239000003306 quinoline derived antiinfective agent Substances 0.000 claims 2
- 230000002378 acidificating effect Effects 0.000 claims 1
- 150000001447 alkali salts Chemical class 0.000 claims 1
- 239000001913 cellulose Substances 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 description 22
- 238000000889 atomisation Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 239000000845 maltitol Substances 0.000 description 4
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 4
- 235000010449 maltitol Nutrition 0.000 description 4
- 229940035436 maltitol Drugs 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920003148 Eudragit® E polymer Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000011149 active material Substances 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- MRBKEAMVRSLQPH-UHFFFAOYSA-N 3-tert-butyl-4-hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1 MRBKEAMVRSLQPH-UHFFFAOYSA-N 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 229920003149 Eudragit® E 100 Polymers 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
PHARMACEUTICAL FORMULATION HAVING A MASKED TASTE AND METHOD FOR THE PRODUCTION THEREOF wton ii*?> iiiwtt o u va mhp wsty Eitan, Pearl, Latzer & Cohen-Zedek P-6403-IL PHARMACEUTICAL FORMULATION WITH A MASKED TASTE AND A PROCESS FOR ITS PREPARATION A subject of the present invention is a pharmaceutical formulation in the form of a powder intended for oral administration in an aqueous suspension, having a masked taste, a process for its preparation and a method for masking the taste of pharmaceutical products.
It is well known that numerous pharmaceutical products intended for oral administration have a very unpleasant taste and sometimes a very high persistence. This is the case in particular with antibiotic products commonly called by the name of macrolides or macrolide-like, such as ketolides, or of cephalosporins or quinolones . This of course assumes a particular importance in the case where the said pharmaceutical products are intended to be administered to children .
Several processes for masking the taste of pharmaceutical products have been described in the literature. These processes most often consist of covering the microparticles of products with a film which disappears after passage through the mouth. There may be mentioned, for example, the article by Roy "Taste masking in oral pharmaceuticals", Pharmaceutical Technology - April 1994 - p. 84 - 99 or the Patent Application WO 98/14179. There are also processes in which the active materials are included in materials which allow their release in the body under defined conditions. Such matrices are described, for example, by C. Brossard in Actualites Pharmaceutiques - No. 388 - July-August 2000,- or in the Patent Applications WO 99/08660, WO 99/17742 or EP 1027887.
One problem to be solved in the case of a matrix is to ensure that the bioavailability of the active material included in a matrix remains acceptable, taking into account the fact that the components (excluding the active ingredient) of the matrix which can be used are not necessarily favourable, for various inherent reasons .
A subject of the present invention is a pharmaceutical formulation having a masked taste, the masking of which persists during administration of the formulation, in particular in the form of a suspension in an aqueous vehicle, characterized in that it comprises at least the following elements: a) - a cellulosic polymer which is soluble in organic solvents but practically insoluble in water, regardless of the pH; - a methacrylic polymer which is soluble in an acid medium and practically insoluble at a neutral or alkaline pH and - an active ingredient distributed in a homogeneous manner and in the molecular state in the mixture, which is in the form of an atomized matrix; b) an alkaline agent of an organic nature, or an alkaline salt, which is pharmaceutically acceptable; c) an adsorbent agent.
As indicated above, the formulation according to the invention is intended to be suspended in water and then, where appropriate, stored in this state for some days, in practice 5 to 10 days, during its absorption period.
It is important to note that each of the three elements of the formulation cooperates with the other two, but that the entirety of the three elements, however, is essential to obtain the required effect of masking the taste at the time of absorption of the formulation according to the invention.
In a non-limitative manner, the various constituents of the formulation according to the invention, which must of course be pharmaceutically acceptable, can be chosen as follows: The cellulosic polymer is, in particular, ethylceliulose . It must be soluble in the organic solvents used in the process according to the invention and as insoluble as possible in water, regardless of the pH.
The methacrylic polymer must be soluble in water at an acid pH (5 or less than 5) and as insoluble as possible at a neutral and alkaline pH, and its function is firstly to ensure that only the relatively small proportion of the active ingredient present on the surface of the microparticles which make up the formulation are accessible to dissolution after being suspended in water for the purpose of absorption, and secondly to ensure a good bioavailability of the active ingredient after its ingestion. It is chosen, in particular, from polymers which are known by the name Eudragit E and are available from the company Rohm Pharma GmbH, these being cationic polymers formed from 2-dimethylaminoethyl methacrylate and neutral methacrylates .
The alkaline agent ensures an alkaline pH in the formulation after suspension thereof in water for the purpose of its absorption, and ensures that the majority of the active ingredient dispersed in the matrix remains inaccessible to dissolution after suspension in water. In acting in this manner, it contributes towards limiting the unpleasant taste. It is chosen, in particular, from the group consisting of meglumine, lysine and sodium and potassium citrate and carbonate .
The adsorbent agent ensures adsorption on its surface of the amounts of active ingredient released after suspension of the formulation in water, while allowing its release in the stomach and thus ensuring its good bioavailability. In acting in this manner, it also contributes towards limiting the unpleasant taste. It is chosen, in particular, from talc and magnesium aluminium silicate, the latter being more particularly preferred, in particular in a fine particle size .
The active ingredient can be, in particular, an antibiotic of the macrolide or macrolide-like type, that is to say erythromycin and its derivatives, such as, for example, roxithromycin, telithromycin, azithromycin or clarithromycin, or of the cephalosporin, penicillin, tetracycline or quinolone type, but also any other type of substance administered orally and having an unpleasant taste which is required to be masked, as long as it has a sufficient solubility in the organic solvent used in the preparation of the formulation.
A particular subject of the present invention is a formulation as defined above, characterized in that the active ingredient is an antibiotic of the macrolide or macrolide-like type such as those mentioned above, and more particularly, a ketolide such as telithromycin. This compound is described, for example, in European Patent EP 0 680 967.
The cellulosic polymer is present in the atomized matrix in a proportion which preferably ranges from 30 % to 50 % by weight, and the methacrylic polymer is present in a proportion of 10 % to 25 % by weight. The active ingredient is present in the atomized matrix at a maximum level of 50 % by weight .
A more particular subject of the present invention is a formulation as defined above, characterized in that the proportions of cellulosic and methacrylic polymers in the matrix range respectively from 40 % to 45 % and from 15 % to % by weight, and in that the proportion of the active ingredient in the matrix ranges up to 30 % by weight.
It is acknowledged that for a product such as telithromycin, a concentration of 10 μΐ/ml is already unacceptable because of its unpleasant taste and its very high persistence. Taking into account the significant amount of the active ingredient which is present on the surface of the microparticles of the matrix and which consequently is accessible to dissolution, that is to say an amount which is very much greater than the μΐ/ml above, it is thus surprising that masking of the taste is already obtained by simple "imprisonment" in the matrix.
The formulation according to the invention can also comprise one or more other elements known individually to a person skilled in the art, in particular a hydrophobic plasticizing agent and an antioxidant agent, as regards the matrix itself, and one or more preservative agents, one or more sweetening agents, a thickening agent, and one or more flavouring agents.
The above elements can be chosen, in particular, as follows: The hydrophobic plasticizing agent is, for example, dibutyl sebacate or diethyl phthalate.
The antioxidant agent is, for example, a-tocopherol , BHT or 2 , 6-di-tert-butyl-4-methylphenol or BHA or 2-tert-butyl-4-methoxyphenol .
The preservative agent is, for example, methyl or propyl parahydroxybenzoate .
The sweetening agent or agents are chosen from those which are usually used in the pharmaceuticals or foodstuffs industry, for example maltitol, sodium saccharinate or saccharose .
The thickening agent is, for example, a xanthan gum or the sodium salt of carboxymethylcellulose .
The flavouring agent or agents are chosen from those which are usually used in the pharmaceuticals or foodstuffs industry .
It is known that a compound such as ethylcellulose which is insoluble in water, regardless of the pH, if present inside a matrix reduces the bioavailability of the active ingredient by impeding its diffusion towards the mucous membranes where it is absorbed.
It is also known that an adsorbent agent such as magnesium aluminium silicate also reduces the bioavailability of an active ingredient due to the potent adsorption effect which manifests itself on its surface (see, for example, Handbook of Pharmaceutical Excipients p. 269-273,7, 11 and 12 (1994)).
A person skilled in the art therefore should not be prompted to use such compounds to formulate an active ingredient under the conditions of the invention.
The beneficial effect of masking of taste obtained by means of the use in pharmaceutical formulations of such compounds should thus logically be adversely affected by the reduced bioavailability of the active ingredient, and it should thus be expected that the formulation according to the invention has a delayed effect as regards the therapeutic efficacy of the active ingredient. In fact, this is not the case and, unexpectedly, the formulation on the contrary demonstrates a very good in vivo bioavailability of the active ingredient while masking the bad taste in amounts which are quite remarkable .
It has thus been found in tests in vivo that the bioavailability can range from 60 to 100 % in the case of traditional tablets, and indeed can be better with a proportion which can reach about 30 %.
A subject of the present invention is also a process for the preparation of a pharmaceutical formulation as defined above, characterized in that a cellulosic polymer and a methacrylic polymer as defined above and, where appropriate, a plasticizing agent and an antioxidant agent as defined above are mixed in an organic solvent, the active ingredient is then added, the solution obtained is then passed through an atomizer to obtain a powder in the form of an atomized matrix, the said powder is mixed with an alkaline agent and an adsorbent agent as defined above and, where appropriate, with one or more elements chosen from the group consisting of preservative agents, sweetening agents, thickening agents and flavouring agents as defined above, and the expected formulation is obtained.
The organic solvent is chosen such that it is a good solvent simultaneously for the cellulosic polymer, the methacrylic polymer, the active ingredient and, where appropriate, the plasticizing and antioxidant agents. It is thus possible to use, in particular, solvents such as halogenated hydrocarbons, in particular methylene chloride, alcohols, in particular ethanol and isopropanol, and ketones, in particular acetone and methyl ethyl ketone.
A subject of the present invention is also a process for masking the taste of a pharmaceutical active ingredient intended for oral administration in an aqueous suspension, characterized in that the said active ingredient is imprisoned homogeneously inside a matrix comprising at least a cellulosic polymer and a methacrylic polymer as defined above and is combined there with at least an alkaline agent and an adsorbent agent as defined above.
The following example illustrates the invention, without however limiting it: 1/ Preparation of a solution for atomization The following starting ingredients are used: The procedure is as follows The dibutyl sebacate, a-tocopherol , Eudragit E 100® and ethylcellulose N10 are introduced into 20 litres of methylene chloride with moderate agitation. Agitation is continued overnight .
One hour before the start of the atomization, the telithromycin is dissolved in the solution of polymers and the solution is made up to the desired weight with methylene chloride . 2/ Atomization The operation is carried out in an atomizer in accordance with the following parameters: Inlet temperature: 85 °C Outlet temperature: 45-55°C Two-fluid of single-fluid nozzle The nozzle and the drying chamber are placed entirely under nitrogen. 3/ Secondary drying The atomization product is spread out on plates and placed in an oven under a flow of nitrogen at room temperature for 24 hours.
An atomization product comprising 30 % active ingredient is finally obtained. 4/ Preparation of the final mixture (1) Magnesium aluminium silicate of fine particle size. (2) Xanthan gum (3) P 90 designates a particular particle size of the maltitol .
A so-called "return" mixer is used.
Before the products are introduced into the mixer, they are passed through a sieve with a mesh opening of 850 μπι. Mixing is then carried out as follows: - Premixing: all the excipients and only 1/3 of the maltitol are mixed for 10 minutes at 20 rpm; - Mixing: the remainder of the maltitol and the atomization product are then mixed for 30 minutes at 20 rpm.
The final mixture is then distributed into the bottles.
It should be noted that the names Eudragit E, Veegum F and Rhodigel ultra are registered trade marks.
Claims (18)
1. Pharmaceutical formulation with a masked taste, the masking of which persists during the administration of the formulation, especially in the form of a suspension in an aqueous vehicle, characterized in that it contains at least the following components : a) - a cellulose-based polymer that is soluble in organic solvents but virtually insoluble in water irrespective of the pH; a methacrylic polymer that is soluble in acidic medium and virtually insoluble at neutral or alkaline pH, and an active principle uniformly distributed and in molecular form in the mixture, which is in the form of an atomized matrix; b) a basic agent of organic nature or a' pharmaceutically acceptable basic salt; c) an adsorbent.
2. Formulation according to Claim 1, characterized in that the cellulose-based polymer and the methacrylic polymer are, respectively, ethylcellulose and a cationic polymer formed from 2-dimethylaminoethyl methacrylate and neutral methacrylates.
3. Formulation according to Claim 1 or 2, characterized in that the basic agent and the adsorbent are chosen, respectively, from the group consisting of meglumine, lysine, sodium citrate, potassium citrate, sodium carbonate and potassium carbonate, and from the group consisting of magnesium aluminium silicate and talc.
4. Formulation according to Claim 3, characterized in that the basic agent and the adsorbent are, respectively, meglumine and magnesium aluminium silicate. 11 159404/2
5. Formulation according to any one of Claims 1 to 4, characterized in that the active principle is a macrolide or macrolide-like , cephalosporin, penicillin, tetracycline or quinolone antibiotic.
6. Formulation according to Claim 5, characterized in that the active principle is a ketolide.
7. Formulation according to Claim 5, characterized in that the active principle is telithromycin .
8. Formulation according to any one of Claims 1 to 7, characterized in that: the cellulose-based polymer is present in the atomized matrix in a proportion ranging from 30% to 50% by weight, and the methacrylic polymer in a proportion ranging from 10% to 25% by weight, and the active principle is present in the atomized matrix upto a proportion of 50% by weight.
9. Formulation according to Claim 8, characterized in that the proportions of cellulose-based and methacrylic polymers in the matrix range from 40% to 45% and from 15% to 20% by weight, respectively, and in that the proportion of the active principle is upto 30% by weight.
10. Formulation according to any one of Claims 1 to 9, characterized in that it also contains in the matrix a hydrophobic plasticizer and/or an antioxidant.
11. Formulation according to any one of Claims 1 to 10, characterized in that it also contains one or more components chosen from preserving agents, sweeteners, thickeners and flavourings . 12 159404/2
12. Process for preparing a pharmaceutical formulation as defined in any one of Claims 1 to 11, characterized in that a cellulose-based polymer and a methacrylic polymer as defined in Claim 1 and, where appropriate, a hydrophobic plasticizer and an antioxidant are mixed together in an organic solvent, the active principle is then added, the solution obtained is then placed in an atomizer to obtain a product in the form of an atomized matrix, the said powder is mixed with a basic agent and an adsorbent and, where appropriate, with one or more components chosen from the group consisting of preserving agents, sweeteners, thickeners and flavourings, and the •expected formulation is obtained.
13. Process according to Claim 12, characterized in that the organic solvent used is chosen from the group consisting of halogenated hydrocarbons, alcohols and ketones.
14. Process according to Claim 13, characterized in that the solvent is methylene chloride.
15. Process according to Claim 12, characterized in that the active principle is a macrolide or macrolide-like antibiotic or a cephalosporin, penicillin, tetracycline or quinolone antibiotic .
16. Process according to Claim 15, characterized in that the active principle is a ketolide.
17. Process according to Claim 15 or 16, characterized in that the active principle is telithromycin.
18. Process according to Claim 12, characterized in that the basic agent and the adsorbent are chosen, respectively, from the group consisting of meglumine, lysine, sodium and potassium citrate and carbonate, and from the group consisting of talc and magnesium aluminium silicate. 13 159404/2 Process for masking the taste of a pharmaceutical product for oral administration as an aqueous suspension, characterized in that the said active principle is uniformly enclosed within a matrix consisting of at least one cellulose-based polymer and one methacrylic polymer as defined in Claim 1, and at least one basic agent as defined in Claim 1 and an adsorbent are combined therewith . the Applicant, Pearl Cohen Zedek Latzer Advocates, Patent Attorneys & Notaries P-6403-IL
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| FR0108157A FR2826274B1 (en) | 2001-06-21 | 2001-06-21 | PHARMACEUTICAL FORMULATION FOR MASK TASTE AND METHOD FOR PREPARING THE SAME |
| PCT/FR2002/002158 WO2003000225A2 (en) | 2001-06-21 | 2002-06-21 | Pharmaceutical formulation having a masked taste and method for the production thereof |
Publications (1)
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| IL159404A true IL159404A (en) | 2007-08-19 |
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| IL159404A IL159404A (en) | 2001-06-21 | 2003-12-16 | Pharmaceutical formulation having a masked taste and method for the production thereof |
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| IL15940402A IL159404A0 (en) | 2001-06-21 | 2002-06-21 | Pharmaceutical formulation having a masked taste and method for the production thereof |
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| US7384921B2 (en) * | 2004-02-20 | 2008-06-10 | Enanta Pharmaceuticals, Inc. | Polymorphic forms of 6-11 bicyclic ketolide derivatives |
| GB2419094A (en) * | 2004-10-12 | 2006-04-19 | Sandoz Ag | Pharmaceutical composition of unpleasnt tasing active substances |
| FR2882522B1 (en) * | 2005-02-25 | 2007-04-13 | Aventis Pharma Sa | SOLID PHARMACEUTICAL COMPOSITION COMPRISING TELITHROMYCIN |
| US7384922B2 (en) * | 2005-05-04 | 2008-06-10 | Enanta Pharmaceuticals, Inc. | 6-11 bridged oxime erythromycin derivatives |
| US20060264386A1 (en) * | 2005-05-17 | 2006-11-23 | Rongqi Sun | Pharmaceutical formulations of 6-11 bicyclic ketolide derivatives and related macrolides and methods for preparation thereof |
| CA2641351C (en) * | 2006-02-03 | 2014-05-06 | Christian Meier | Pharmaceutical compositions containing mixtures of polymers and active agents poorly soluble in water |
| US20100226979A1 (en) * | 2006-03-21 | 2010-09-09 | Jubilant Organosys Limited | Taste Masked Phamaceutical Composition for Oral Solid Dosage form and Process for Preparing the Same Using Magnesium Aluminium Silicate |
| WO2008094877A2 (en) * | 2007-01-30 | 2008-08-07 | Drugtech Corporation | Compositions for oral delivery of pharmaceuticals |
| KR100935893B1 (en) * | 2007-09-11 | 2010-01-07 | 국방과학연구소 | Synthesis of 1,1'-dimethyl-5,5'-bitetrazole |
| WO2009055557A1 (en) | 2007-10-25 | 2009-04-30 | Cempra Pharmaceuticals, Inc. | Process for the preparation of macrolide antibacterial agents |
| CA2746704C (en) | 2008-12-16 | 2017-08-22 | Carlsberg A/S | Coating of hydroxylated surfaces by gas phase grafting |
| HK1205939A1 (en) | 2012-03-27 | 2015-12-31 | Cempra Pharmaceuticals, Inc. | Parenteral formulations for administering macrolide antibiotics |
| DE102012014848A1 (en) * | 2012-07-27 | 2012-10-31 | Heilerde-Gesellschaft Luvos Just GmbH & Co. KG | Healing clay-composition present as non-coated or as coated granules, comprises healing clay and binding agent containing at least one water soluble polymer e.g. starch, tragacanth or cellulose acetate, cellulose ether |
| JP2017523975A (en) * | 2014-08-05 | 2017-08-24 | センプラ ファーマシューティカルズ，インコーポレイテッド | Oral antibacterial powder suspension formulation |
| US10982177B2 (en) | 2017-09-18 | 2021-04-20 | The Clorox Company | Cleaning wipes with particular lotion retention and efficacy characteristics |
| CN114209661B (en) * | 2022-02-21 | 2022-04-29 | 北京罗诺强施医药技术研发中心有限公司 | Solid pharmaceutical composition in the form of granules |
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| DE2930409A1 (en) * | 1979-07-26 | 1981-02-12 | Bayer Ag | SPRAY DRYING OF MICROCAPSEL DISPERSIONS |
| JPS63150220A (en) * | 1986-12-15 | 1988-06-22 | Dainippon Pharmaceut Co Ltd | Preparation of solid drug for oral administration |
| US4808411A (en) * | 1987-06-05 | 1989-02-28 | Abbott Laboratories | Antibiotic-polymer compositions |
| US5084278A (en) * | 1989-06-02 | 1992-01-28 | Nortec Development Associates, Inc. | Taste-masked pharmaceutical compositions |
| ZA945944B (en) * | 1993-08-13 | 1996-02-08 | Eurand America Inc | Procedure for encapsulating nsaids |
| AUPN969796A0 (en) * | 1996-05-07 | 1996-05-30 | F.H. Faulding & Co. Limited | Taste masked liquid suspensions |
| AU9182498A (en) * | 1997-10-03 | 1999-04-27 | Elan Corporation, Plc | Taste masked formulations |
| IN191239B (en) * | 1999-06-11 | 2003-10-11 | Ranbaxy Lab Ltd | |
| US6555569B2 (en) * | 2000-03-07 | 2003-04-29 | Pfizer Inc. | Use of heteroaryl substituted N-(indole-2-carbonyl-) amides for treatment of infection |
| DE60135859D1 (en) * | 2000-08-22 | 2008-10-30 | Basilea Pharmaceutica Ag | NEW MACROLIDE WITH ANTIBACTERIAL EFFECT |
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- 2002-06-21 AU AU2002329311A patent/AU2002329311B2/en not_active Ceased
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